Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is
considered to be an extreme variant of pulmonary thromboembolism. The
underlying mechanisms for the failure of thrombus resolution are still
unclear. In looking for inherited thrombophilia, an association with a
lupus anticoagulant has been described repeatedly, and single cases of
anticoagulant deficiencies (ie, antithrombin [AT],
protein C, and protein S) have been reported. We describe a young
patient with type I AT deficiency, the heterozygous prothrombin G20210A
mutation, and unilateral chronic thromboembolic pulmonary disease
presenting after a single thrombotic event. Pulmonary vascular patency
was restored successfully by surgical pulmonary thromboendarterectomy.
This case is unique because unilateral CTEPH is extremely uncommon, and
it illustrates the severe clinical sequelae of the cosegregation of
inherited thrombophilic defects. (CHEST 2002;
121:286–289)

Figures in this Article

Chronic
thromboembolic pulmonary hypertension (CTEPH) is an
aberrant outcome of pulmonary embolism (PE) that is due to inadequate
thrombus dissolution.1CTEPH has been found to be present
in about 1 to 3% of autopsy series.2–3 The clinical
incidence is estimated to range between 0.01% and 0.5% of embolic
events.1,3The particular causes for the failure of
embolus resolution have not been identified. Although abnormalities in
the fibrinolytic system have been implicated as the reason for the
failure of thrombus resolution,4 the pathogenesis of CTEPH
remains obscure. Prothrombotic coagulation disorders initially have
been found in a small proportion of CTEPH patients,1 and
not until recently has thrombophilia been investigated. The presence of
the lupus anticoagulant has been diagnosed in up to 30% of CTEPH
patients.5–8 Deficiencies of antithrombin (AT), protein
S, or protein C have been identified in about 1% of
cases.1,5–7 Knowledge of inherited thrombophilia has
significantly increased during the last decade, and prothrombotic
abnormalities can be detected in more than half of the patients with
venous thromboembolism (VTE).9 Based on these data, the
thromboembolic nature of CTEPH has been questioned. We report on a
young patient with the joint occurrence of type I AT deficiency and a
heterozygous prothrombin G20210A mutation (FII G20210A), who developed
CTEPH with total occlusion of the right pulmonary artery.

Case Report

A 19-year-old white woman first presented to a hospital outside
of our institution in November 1998 with the sudden onset of
acute dyspnea and chest pain. A diagnosis of acute PE was confirmed by
spiral CT scan, demonstrating a total occlusion of the right pulmonary
artery with a saddle thrombus in the presence of a small right-sided
pleural effusion. A lung scan revealed a complete right-sided
ventilation-perfusion mismatch. The results of color-coded duplex
sonography of both legs were normal. The patient was obese, had a
history of smoking 30 cigarettes per day, and had used a
third-generation oral contraceptive. During her initial
hospitalization, treatment consisted of high-dose IV unfractionated
heparin (Heparin; Immuno AG; Vienna, Austria), 5,000-U bolus followed
by a continuous infusion of 1,000 U/h, followed by oral anticoagulation
therapy with phenprocoumon (Marcoumar; Hoffmann-La Roche; Basel,
Switzerland) [international normalized ratio target range, 2 to 3].
The patient was referred to our institution for further monitoring of
oral anticoagulation therapy and a thorough diagnostic workup of
thrombophilia 3 months after the incident.

The laboratory evaluation (Table 1
) revealed a type 1 AT deficiency (ie, AT activity, 50% [as
determined by chromogenic substrate analysis; Stago; Assignieres,
France]; AT antigen level, 48% [as determined by Laurell
immunoelectrophoresis; Dakopatts; Älvsjö, Sweden]).
On a molecular level, a nonsense mutation in codon 197 arginine to stop
(exon 3B), and a C-to-T transition at nucleotide position 6490 (CGA to
TGA) was identified.10The second instance of
thrombophilia that was found was a heterozygosity for the prothrombin
gene G20210A variant, as detected by polymerase chain
reaction.11The results of additional screening
investigations, including that for the factor V Leiden (FVL)
mutation,12 and coagulation assays, which were carried out
by standard protocols, were normal. Fibrinolytic parameters for tissue
plasminogen activator, plasminogen activator inhibitor, and
plasmin-antiplasmin complex were within the normal range.

A family study showed a maternal inheritance of the FII G20210A mutant.
No data from the patient‘s father and his kindred were available. A
family history of the maternal kindred was unremarkable for VTE, but
the patient‘s mother had experienced a myocardial infarction at 23
years of age.

Despite temporary clinical improvement and initial signs of thrombus
regression on follow-up CT scans, the patient‘s clinical status
deteriorated to a New York Heart Association functional class III
status. Cardiovascular reevaluation after her referral revealed CTEPH
with invasively measured borderline pulmonary artery pressures at rest
(systolic BP, 43 mm Hg; diastolic BP, 12 mm Hg; mean, 28 mm Hg)
and a calculated pulmonary vascular resistance at rest of 390
dyne · s · cm−5. Digital subtraction
angiography showed a total occlusion of the right pulmonary artery at
the level of the mainstem. A lung scan disclosed a lack of perfusion to
the occluded side. Pulmonary vascular patency was successfully restored
by pulmonary thromboendarterectomy (PTE).13
Intraoperatively, total unilateral thrombotic occlusion of the right
main pulmonary artery was found. The surgical specimen was a white,
organized thromboembolus, as shown in Figure 1
. In order to minimize the risk for further VTE, AT concentrates
(target range, 120% activity) were substituted throughout the
perioperative period, and oral anticoagulation was restarted on day 10
after PTE. PTE resulted in normal reperfusion and in an immediate and
persistent hemodynamic and functional improvement toward a New
York Heart Association functional class I status. At the 16-month
postdischarge follow-up, the patient had normal results for a lung
perfusion scan performed while receiving oral anticoagulation therapy,
which will be maintained lifelong.

Discussion

We present a rare case of unilateral chronic thromboembolic
pulmonary arterial occlusion associated with a rare combined
thrombophilic defect. The natural history of PE is either a
total resolution of the condition or resolution leaving only minimal
residua with restoration of normal pulmonary hemodynamics within weeks
to several months.1 In a small subgroup of patients, this
resolution does not occur. Clinically, CTEPH developed in this case
after a single clinical thromboembolic event with serial CT scans
demonstrating the regression of a saddle thrombus after 12 weeks of
oral anticoagulation therapy. The surgical specimen that was obtained
24 weeks after the initial clinical presentation was a white organized
tissue mass occluding the right pulmonary mainstem (Fig 1). Thus,
complete organization of the thrombus must have proceeded within
several weeks. Because AT exerts an anti-inflammatory
effect,,14one may speculate that the underlying AT
deficiency may have contributed to this unusual pattern of thrombus
organization on a cellular level. Given the fact that the
pathophysiology of CTEPH is a vast area of speculation, the
contribution of multifunctional molecules such as AT to abnormal
thrombus organization deserves consideration. Hemodynamic evaluation
showed almost normal pulmonary vascular resistance at rest, according
to the typical presentation of unilateral disease.15
Furthermore, the patient displayed the typical features of unilateral
disease, as she was young and a woman. In the only
reported15 cohort of patients with unilateral disease
undergoing PTE, recurrent postoperative thrombosis occurred in 4 of 11
patients, and inadequate perfusion occurred in 6 of 11 patients. Few
data exist on the long-term results of PTE in patients with
thrombophilia.5–6 Our patient had normal perfusion of the
right lung 16 months post PTE.

VTE is now regarded as a multicausal process and occurs only when two
or more risk factors are present.9 Inherited deficiencies
of natural coagulation inhibitors such as AT, protein C, and protein S
are rare with a prevalence in VTE patients of approximately
5%.9 AT-deficient patients carry a risk of VTE of about 7
to 10%,9 and about half of them experience their first
thrombotic event before 25 years of age. The coincidence of natural
anticoagulant deficiencies with CTEPH was found to be only
approximately 1%.1 Small series have reported higher
prevalences,5–8 but almost all investigations date from a
period prior to the discovery of thrombophilic genetic point mutations
such as FII G20210A. This transition, located in the 3′-untranslated
region of the prothrombin gene (ie, prothrombin 20210 G′A),
increases the thrombotic risk, probably through enhanced plasma
prothrombin levels.,11 The incidence of this mutation in
the white population varies between 0.7% and 3.8% and confers a
relative risk of VTE of about 2.0.11In contrast to the
most common cause of congenital thrombophilia, a point mutation at
position 1691 in the factor V gene (ie,
FVL),12,16FII G20210A has been proposed as being an
independent risk factor for PE.17Whereas FVL is not
associated with CTEPH,18the occurrence of FII G20210A in
CTEPH patients has not yet been reported. The calculated prevalence for
the combination of congenital type 1 AT deficiency and the FII G20210A
mutation is estimated to be approximately 1 in 500,000
cases.19So far, only four cases of such a combination of
AT deficiency and the heterozygous FII G20210A mutation have been
reported.20–21 It seems that the concomitant presence of
FII G20210A renders patients with inherited thrombophilia more
susceptible to thrombotic episodes, but more reliable information about
the interaction of FII G20210A with other prothrombotic effects is
required.

The greatest progress in the management of CTEPH is the clinical
awareness of the disease and the diagnostic workup of surgical thrombus
accessibility.1,5–7 The present case is unique in that it
demonstrates a rare combined thrombophilic defect underlying severe
unilateral CTEPH. To this date, no knowledge exists on the precise
mechanism causing CTEPH. Although a combined coagulation defect found
in only 1 of 500,000 patients is unlikely to have a great bearing even
on a rare disease such as CTEPH, this case illustrates a potential
pathophysiologic contribution of plasmatic coagulation and
thromboembolism in patients with CTEPH.

Poort, SR, Rosendaal, FR, Reitsma, PH, et al A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.Blood1996;88,3698-3703. [PubMed]

Poort, SR, Rosendaal, FR, Reitsma, PH, et al A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.Blood1996;88,3698-3703. [PubMed]

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